Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

Abstract Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun−/−), Ddit3 null (Ddit3−/−), and Ddit3−/−Jun−/− mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation.

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Decreased TNF Levels and Improved Retinal Ganglion Cell Survival in MMP-2 Null Mice Suggest a Role for MMP-2 as TNF Sheddase

Mediators of Inflammation ◽

10.1155/2015/108617 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 9

Author(s):

Lies De Groef ◽

Manuel Salinas-Navarro ◽

Griet Van Imschoot ◽

Claude Libert ◽

Roosmarijn E. Vandenbroucke ◽

...

Keyword(s):

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Retinal Ganglion ◽

Spatiotemporal Expression ◽

Retinal Ganglion Cell Death ◽

The Central Nervous System ◽

Retinal Ganglion Cell Survival ◽

Ganglion Cell Death

Matrix metalloproteinases (MMPs) have been designated as both friend and foe in the central nervous system (CNS): while being involved in many neurodegenerative and neuroinflammatory diseases, their actions appear to be indispensable to a healthy CNS. Pathological conditions in the CNS are therefore often related to imbalanced MMP activities and disturbances of the complex MMP-dependent protease network. Likewise, in the retina, various studies in animal models and human patients suggested MMPs to be involved in glaucoma. In this study, we sought to determine the spatiotemporal expression profile of MMP-2 in the excitotoxic retina and to unravel its role during glaucoma pathogenesis. We reveal that intravitreal NMDA injection induces MMP-2 expression to be upregulated in the Müller glia. Moreover, MMP-2 null mice display attenuated retinal ganglion cell death upon excitotoxic insult to the retina, which is accompanied by normal glial reactivity, yet reduced TNF levels. Hence, we propose a novelin vivofunction for MMP-2, as an activating sheddase of tumor necrosis factor (TNF). Given the pivotal role of TNF as a proinflammatory cytokine and neurodegeneration-exacerbating mediator, these findings generate important novel insights into the pathological processes contributing to glaucomatous neurodegeneration and into the interplay of neuroinflammation and neurodegeneration in the CNS.

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Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance

The Journal of Cell Biology ◽

10.1083/jcb.200405053 ◽

2004 ◽

Vol 167 (4) ◽

pp. 687-698 ◽

Cited By ~ 73

Author(s):

Mayya Meriane ◽

Joseph Tcherkezian ◽

Christine A. Webber ◽

Eric I. Danek ◽

Ibtissem Triki ◽

...

Keyword(s):

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Ganglion Cells ◽

Axon Outgrowth ◽

Retinal Ganglion ◽

Deleted In Colorectal Cancer ◽

Commissural Neurons

Netrin-1 acts as a chemoattractant molecule to guide commissural neurons (CN) toward the floor plate by interacting with the receptor deleted in colorectal cancer (DCC). The molecular mechanisms underlying Netrin-1–DCC signaling are still poorly characterized. Here, we show that DCC is phosphorylated in vivo on tyrosine residues in response to Netrin-1 stimulation of CN and that the Src family kinase inhibitors PP2 and SU6656 block both Netrin-1–dependent phosphorylation of DCC and axon outgrowth. PP2 also blocks the reorientation of Xenopus laevis retinal ganglion cells that occurs in response to Netrin-1, which suggests an essential role of the Src kinases in Netrin-1–dependent orientation. Fyn, but not Src, is able to phosphorylate the intracellular domain of DCC in vitro, and we demonstrate that Y1418 is crucial for DCC axon outgrowth function. Both DCC phosphorylation and Netrin-1–induced axon outgrowth are impaired in Fyn−/− CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1.

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Molecular mechanisms of optic nerve damage: the role of anthocyanozides in the prevention of retinal ganglion cell death

Russian Ophthalmological Journal ◽

10.21516/2072-0076-2018-11-3-101-106 ◽

2018 ◽

Vol 11 (3) ◽

pp. 101-106

Author(s):

V.V. Neroev ◽

◽

T.N. Kiseleva ◽

М.S. Zaitsev ◽

◽

...

Keyword(s):

Cell Death ◽

Optic Nerve ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Molecular Mechanisms ◽

Retinal Ganglion ◽

Optic Nerve Damage ◽

Retinal Ganglion Cell Death ◽

Ganglion Cell Death

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The Role of Neuroinflammation in Glaucoma: An Update on Molecular Mechanisms and New Therapeutic Options

Frontiers in Neurology ◽

10.3389/fneur.2020.612422 ◽

2021 ◽

Vol 11 ◽

Author(s):

Teresa Rolle ◽

Antonio Ponzetto ◽

Lorenza Malinverni

Keyword(s):

Molecular Mechanisms ◽

Ganglion Cells ◽

Experimental Studies ◽

Retinal Ganglion ◽

Cellular Mechanisms ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Ganglion Cell Death ◽

Phosphodiesterase Type

Glaucoma is a multifactorial optic neuropathy characterized by the continuous loss of retinal ganglion cells, leading to progressive and irreversible visual impairment. In this minireview, we report the results of the most recent experimental studies concerning cells, molecular mechanisms, genes, and microbiome involved in neuroinflammation processes correlated to glaucoma neurodegeneration. The identification of cellular mechanisms and molecular pathways related to retinal ganglion cell death is the first step toward the discovery of new therapeutic strategies. Recent experimental studies identified the following possible targets: adenosine A2A receptor, sterile alpha and TIR motif containing 1 (neurofilament light chain), toll-like receptors (TLRs) 2 and 4, phosphodiesterase type 4 (PDE4), and FasL-Fas signaling (in particular ONL1204, a small peptide antagonist of Fas receptors), and therapies directed against them. The continuous progress in knowledge provides interesting data, although the total lack of human studies remains an important limitation. Further research is required to better define the role of neuroinflammation in the neurodegeneration processes that occur in glaucomatous disease and to discover neuroprotective treatments amenable to clinical trials. The hereinafter reviewed studies are reported and evaluated according to their translational relevance.

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Role of C/EBP Homologous Protein in Retinal Ganglion Cell Death After Ischemia/Reperfusion Injury

Investigative Ophthalmology & Visual Science ◽

10.1167/iovs.14-15447 ◽

2014 ◽

Vol 56 (1) ◽

pp. 221-231 ◽

Cited By ~ 29

Author(s):

S. Nashine ◽

Y. Liu ◽

B.-J. Kim ◽

A. F. Clark ◽

I.-H. Pang

Keyword(s):

Cell Death ◽

Ganglion Cell ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Retinal Ganglion ◽

Homologous Protein ◽

Retinal Ganglion Cell Death ◽

Ganglion Cell Death

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Neuroprotective and Anti-Inflammatory Effects of a Hydrophilic Saffron Extract in a Model of Glaucoma

International Journal of Molecular Sciences ◽

10.3390/ijms20174110 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4110 ◽

Cited By ~ 11

Author(s):

Jose A. Fernández-Albarral ◽

Ana I. Ramírez ◽

Rosa de Hoz ◽

Nerea López-Villarín ◽

Elena Salobrar-García ◽

...

Keyword(s):

Cell Death ◽

Intraocular Pressure ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Retinal Ganglion Cell Death ◽

Saffron Extract ◽

Anti Inflammatory ◽

Ganglion Cell Death

Glaucoma is a neurodegenerative disease characterized by the loss of retinal ganglion cells (RGCs). An increase in the intraocular pressure is the principal risk factor for such loss, but controlling this pressure does not always prevent glaucomatous damage. Activation of immune cells resident in the retina (microglia) may contribute to RGC death. Thus, a substance with anti-inflammatory activity may protect against RGC degeneration. This study investigated the neuroprotective and anti-inflammatory effects of a hydrophilic saffron extract standardized to 3% crocin content in a mouse model of unilateral, laser-induced ocular hypertension (OHT). Treatment with saffron extract decreased microglion numbers and morphological signs of their activation, including soma size and process retraction, both in OHT and in contralateral eyes. Saffron extract treatment also partially reversed OHT-induced down-regulation of P2RY12. In addition, the extract prevented retinal ganglion cell death in OHT eyes. Oral administration of saffron extract was able to decrease the neuroinflammation associated with increased intraocular pressure, preventing retinal ganglion cell death. Our findings indicate that saffron extract may exert a protective effect in glaucomatous pathology.

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